| 2018 | Effect of GRM7 polymorphisms on the development of noise-induced hearing loss in Chinese Han workers: a nested case-control study. | BMC Med Genet | Noise-induced hearing loss (NIHL) is a complex, irreversible disease caused by the interaction of genetic and environmental factors. In recent years, a great many studies have been done to explore the NIHL susceptibility genes among humans. So far, high powerful detections have been founded that genes of potassium ion channel genes (KCNQ4 and KCNE1), catalase (CAT), protocadherin 15 (PCDH15), myosin 14 (MYH14) and heart shock protein (HSP70) which have been identified in more than one population may be associated with the susceptibility to NIHL. As for metabolic glutamate receptor7 gene (GRM7), a lot of researches mainly focus on age-related hearing loss (ARHL) and the results have shown that the polymorphisms of GRM7 are linked to the development of ARHL. However, little is known about the association of GRM7 and the susceptibility to NIHL. Therefore, the aim of this study was to explore the effect of GRM7 polymorphisms on the susceptibility to NIHL.A nested case-control study based on the cohort in a Chinese steel factory was implemented in 292 cases and 584 controls matched with the same sex, the age difference ≤ 5 years old, the same type of work, duration of occupational noise exposure ≤2 years. Five single nucleotide polymorphisms (SNPs) of GRM7 were gained through selecting and genotyping SNPs. Conditional logistic regression analysis was used to assess the main effect of GRM7 polymorphisms on the susceptibility to NIHL and the gene-by-environment interaction. Furthermore, the gene-by-gene interactions were analyzed by generalized multiple dimensionality reduction (GMDR).This research discovered for the first time that the mutant allele C in rs1485175 of the GMR7 may decrease individuals' susceptibility to NIHL. The interaction between rs1485175 and cumulative noise exposure (CNE) at high level was found after the stratification according to CNE (p/p = 0.014/0.007, OR = 0.550, 95% CI: 0.340-0.891). Permutation test of GMDR suggested that rs1920109, rs1485175 and rs9826579 in GRM7 might interact with each other in the process of developing NIHL (p = 0.037).The results suggest that the mutant allele C of rs1485175 in GRM7 may reduce the susceptibility to NIHL in Chinese Han population. |
| 2017 | "Homozygous, and compound heterozygous mutation in 3 Turkish family with Jervell and Lange-Nielsen syndrome: case reports". | BMC Med Genet | Jervell and Lange-Nielsen syndrome (JLNS) isa recessive model of long QT syndrome which might also be related to possible hearing loss. Although the syndrome has been demonstrated to be originated from homozygous or compound heterozygous mutations in either the KCNQ1 or KCNE1 genes, additional mutations in other genetic loci should be considered, particularly in malignant course patients.Three patients were admitted into hospital due to recurrent seizures/syncope, intrauterine and postnatal bradycardia respectively; moreover all three patients had congenital sensorineural hearing-loss. Their electrocardiograms showed markedly prolonged QT interval. Implantable defibrillator was implanted and left cardiac sympathetic denervation was performed due to the progressive disease in case 1. She had countless ventricular fibrillation and appropriate shock while using an implantable defibrillator. The DNA sequencing analysis of the KCNQ1 gene disclosed a homozygous c.728G > A (p.Arg243His) missense mutation in case1. Further targeted next generation sequencing of cardiac panel comprising 68 gene revealed a heterozygous c.1346 T > G (p.Ile449Arg) variant in RYR2 gene and a heterozygous c.809G > A (p.Cys270Tyr) variant in NKX2-5 gene in the same patient. Additional gene alterations in RYR2 and NKX2-5 genes were thought to be responsible for progressive and malignant course of the disease. As a result of DNA sequencing analysis of KCNQ1 and KCNE1 genes, a compound heterozygosity for two mutations had been detected in KCNQ1 gene in case 2: a maternally derived c.477 + 1G > A splice site mutation and a paternally derived c.520C > T (p.Arg174Cys) missense mutation. Sanger sequencing of KCNQ1 and KCNE1 genes displayed a homozygous c.1097G > A (p.Arg366Gln) mutation in KCNQ1 gene in case 3. β-blocker therapy was initiated to all the index subjects.Three families of JLNS who presented with long QT and deafness and who carry homozygous, or compound heterozygous mutation in KCNQ1 gene were presented in this report. It was emphasized that broad targeted cardiac panels may be useful to predict the outcome especially in patients with unexplained phenotype-genotype correlation. Clinical presentations and molecular findings will be discussed further to clarify the phenotype genotype associations. |
| 2014 | Regulation of transport across cell membranes by the serum- and glucocorticoid-inducible kinase SGK1. | Mol Membr Biol | The serum- and glucocorticoid-inducible kinase 1 (SGK1) is genomically upregulated by cell stress including energy depletion and hyperosmotic shock as well as a variety of hormones including glucocorticoids, mineralocorticoids and TGFβ. SGK1 is activated by insulin, growth factors and oxidative stress via phosphatidylinositide-3-kinase, 3-phosphoinositide-dependent kinase PDK1 and mTOR. SGK1 is a powerful stimulator of Na(+)/K(+)-ATPase, carriers (e.g., NCC, NKCC, NHE1, NHE3, SGLT1, several amino acid transporters) and ion channels (e.g., ENaC, SCN5A, TRPV4-6, ORAI1/STIM1, ROMK, KCNE1/KCNQ1, GluR6, CFTR). Mechanisms employed by SGK1 in transport regulation include direct phosphorylation of target transport proteins, phosphorylation and thus activation of other transport regulating kinases, stabilization of membrane proteins by phosphorylation and thus inactivation of the ubiquitin ligase NEDD4-2, as well as stimulation of transport protein expression by upregulation transcription factors (e.g., nuclear factor kappa-B [NFκB]) and by fostering of protein translation. SGK1 sensitivity of pump, carrier and channel activities participate in the regulation of epithelial transport, cardiac and neuronal excitability, degranulation, platelet function, migration, cell proliferation and apoptosis. SGK1-sensitive functions do not require the presence of SGK1 but are markedly upregulated by SGK1. Accordingly, the phenotype of SGK1 knockout mice is mild. The mice are, however, less sensitive to excessive activation of transport by glucocorticoids, mineralocorticoids, insulin and inflammation. Moreover, excessive SGK1 activity contributes to the pathophysiology of hypertension, obesity, diabetes, thrombosis, stroke, inflammation, autoimmune disease, fibrosis and tumor growth. |
| Contribution of genetic factors to noise-induced hearing loss: a human studies review. | Mutat Res | Noise-induced hearing loss (NIHL) is a complex disease that results from the interaction of genetic and environmental factors. Over the last 10 years there has been a great increase in association studies trying to identify the susceptibility genes for NIHL in humans. They were conducted based on the candidate gene approach and comprised predominantly the group of oxidative stress genes, inner ear potassium recycling pathway genes and monogenic deafness genes, as well as other genes. So far, the most promising results were obtained for two genes encoding potassium ion channels (KCNQ4 and KCNE1), catalase (CAT), protocadherin 15 (PCDH15), myosin 14 (MYH14) and heat shock protein (HSP70), because they were replicated in two (Polish and Swedish) or three (Polish, Swedish and Chinese) populations, and were sufficient in size to yield high power for the detection of a causative allele. Today, the development of high-throughput genotyping methods allows the detection of hundreds and thousands of single nucleotide polymorphisms (SNPs) in a single array which undoubtedly will lead toward identification of new NIHL susceptibility genes. This in turn will contribute to the development of genetics tests that would allow for better protection of noise-exposed individuals and personalized treatment, if necessary. |
| 2004 | Volume regulation is defective in renal proximal tubule cells isolated from KCNE1 knockout mice. | Exp Physiol | The membrane protein KCNE1 has been implicated in cell volume regulation. Using a knockout mouse model, this study examined the role of KCNE1 in regulatory volume decrease (RVD) in freshly isolated renal proximal tubule cells. Cell diameter was measured using an optical technique in response to hypotonic shock and stimulation of Na(+)-alanine cotransport in cells isolated from wild-type and KCNE1 knockout mice. In HEPES buffered solutions 64% of wild-type and 56% of knockout cells demonstrated RVD. In HCO3- buffered solutions 100% of the wild-type cells showed RVD, while in the knockout cells the proportion of cells displaying RVD remained unchanged. RVD in the knockout cells was rescued by valinomycin, a K+ ionophore. In wild-type HCO3- dependent cells the K+ channel inhibitors barium and clofilium inhibited RVD. These data suggest that mouse renal proximal tubule is comprised of two cell populations. One cell population is capable of RVD in the absence of HCO3-, whereas RVD in the other cell population has an absolute requirement for HCO3-. The HCO3- dependent RVD requires the normal expression of KCNE1. |